4-(1{40 -Alkyl-5{40 -nitroimidazolyl-2{40 -methylene -imino)-tetrahydro-1,4-thiazine-1,1-dioxides and process for their manufacture

ABSTRACT

4-(1&#39;&#39;-ALKYL-5&#39;&#39;-NITROIMIDAZOLYL-2&#39;&#39;-METHYLENE-IMINO)-TETRAHYDRO1,4-THIAZINE 1,1-DIOXIDES OF THE FORMULA   IN WHICH R1 is hydrogen, methyl, ethyl, or 2-hydroxy-ethyl and R2 is hydrogen, methyl, ethyl or methoxymethyl, are prepared by reaction of 1-alkyl-5-nitroimidazolyl-2-aldehyde or a functional derivative thereof with 4-amino-tetrahydro-1,4-thiazine 1,1dioxide. The products of the invention are suitable for the treatment of protozoal diseases.

United States Patent 1 Winkelmann et al.

[ 51 May 20, 1975 4-( l '-ALKYL-5 '-NITROIMlDAZOLYL-2 METHYLENE-IMINO)-TETRAI'IYDRO-1,4-THIAZINE-1,1- DIOXIDES AND PROCESS FOR THEIRMANUFACTURE [75] Inventors: Erhardt Winkelmann, Kelkheim,

' Taunus; Wolfgang Raether,

Dreieichenhain, both of Germany [73] Assignee: HoechstAktiengesellschaft,

Frankfurt, Germany [22] Filed: Dec. 19, 1973 [21] Appl. No.: 425,979

[30] Foreign Application Priority Data Dec. 21, 1972 Germany 2262553[52] US. Cl 260/240 G; 424/246, 260/243 B;

260/243 R [51] Int. Cl. C07d 49/36; C09b 23/00 [58] Field of Search260/240 G, 240 A [56] References Cited UNITED STATES PATENTS 2/1972l-lenry et al. 260/240 G l/l974 llvespaa 260/240 G FOREIGN PATENTS ORAPPLICATIONS 3257M 4/l965 France 260/240 A l,l70,957 l2/l964 Germany I.260/240 A Primary Examiner-John D. Randolph Attorney, Agent, orFirm-Curtis. Morris & Safford [57] ABSTRACT 4-( l'-alkyl-5'-nitroimidazolyl-2-methylene-imino tetrahydro-l,4-thiazine1,1-dioxides of the formula 7 Claims, No Drawings 1 4-(1 '-ALKYL-5'-NITROIMIDAZOLYL-2 METHYLENE -IMINO)-TETRAHYDRO-1 ,4-THIAZINE-1 ,1-

DIOXIDES AND PROCESS FOR THEIR MANUFACTURE in which R, stands for ahydrogen atom, a methyl, ethyl or 2-hydroxy-ethyl group and R for ahydrogen atom, a methyl, ethyl or methoxymethyl group.

The novel compounds have a pronounced activity against trichomonads andamebae, which is superior to the S-nitroimidazoles mentioned above.

This invention further relates to a process for the manufacture of4-(l'-alkyl-5'-nitroimidazolyl-2'- methyleneimino)-tetrahydrol,4-thiazinel ,1 -dioxides of the formula I, which comprises reacting anl-alkyl-S- nitroimidazolyl-Z-aldehyde of the formula II, or a functionalderivative thereof,

in which R, is defined as above, with a4-aminotetrahydro-1,4-thiazine-l,l-dioxide of the formula III (III) inwhich R is defined as above.

The reaction is advantageously carried out using equimolar amounts ofthe reactants as well as a solvent or dispersing agent, preferably analcoholic or aqueous solution or a mixture of an alcohol and water. Thechoice and the ratio of the solvents depend on the solubility of thecompounds. As alcohols are used, for example, methanol, ethanol,propanol or isopropanol. The reaction temperature may be in the range offrom to 100C, advantageously from 60 to 80C. It is advantageous to add asmall amount of an acid, for example hydrochloric acid or acetic acid,as a condensation catalyst. Depending on the reaction conditions used,the reaction times are in the range of from a few seconds to severalminutes. In most cases, the reaction products are obtained in the formof crystals of high purity which are isolated in the usual manner bysuctionfiltration. Where required. they may be purified byrecrystallization from a suitable solvent or mixture of solvents.

The 4'( l -alkyl-5'-nitroimidazolyl-2'-mcthylcneimino )-tetrahydro-l,4-thiazine-l l -dioxides are suitable for the treatment of protozoaldiseases in mammals,caused, for example infections with Trichomonasvaginalis and Entamoeba histolytica. The novel compounds of theinvention may be administered orally or locally. For the oral route, thecompounds are usually administered in the form of tablets or capsulescontaining, per daily dosage unit, about 10 to 750 mg of the activesubstance in admixture with a conventional diluent and/or excipient.

For local administration, jellies, creams, ointments or suppositoriesmay be used.

In addition to a very good compatibility, the novel products accordingto the invention are distinguished by a safe activity againsttrichomonads and amoebae, which is superior to the known pharmaceuticalcomposition Metronidazol, as can be seen from the following Tables.

The following Examples serve to illustrate the invention.

EXAMPLE 1 (test for activity):

Activity against Trichomonas foetus was generally tested on home-bredalbino mice (NMRI-strain) of both sexes. The body weight of each animalwas from 10 to 12 grams.

The substance to be tested was administered orally by means of anesophagal sound either in an aqueous solution or, in the case ofsparingly water-soluble compounds, in a Tylose suspension. The overalldosage was administered in two units, the first one two hours prior toinfection and the second one two hours after infection. 4 mice were usedfor each substance to be tested and for each dosage.

Infection was brought about by intraperitoneal injection of 19 millioninfective agents per animal in a suspension in 0.5 ml of a culturemedium, Merck I. The standard Metronidazol was administered by the sameroute and in the same dosage as the substance to be tested (see TableI).

As infection controls were generally used 10 mice which, afterinfection, were not treated any more. Another 5 mice served as a zerocontrol (animals which were not treated and not infected).

Six days after infection, all the test animals were killed and theperitoneal exudate was examined for trichomonads. Mice which had diedbefore were subjected to the same examination.

The tested substance was judged on the concentration of infective agentsto be found in the peritoneal exudate on the 6th day after infection.For this purpose, the concentration of infective agents established withthe tested composition was compared to that of the standard and of theinfection control. The scheme, according to which the tested substanceand the standard were judged with regard to the concentration ofinfectants established, was the following:

ineffective: Concentration of infectants was not substantially reducedas compared to infection control. Judgement: 3; 4 effective: a) faint:Concentration of infectants was moderately reduced as compared toinfection control. Judgement: 2 b) unsatisfactory: Concentration ofinfectants was substantially reduced as compared to infection control.Judgement: I e) no infective agents were to be established.

Judgement:

TABLE 1 Composition dosage in mg/kg concentration of mouse, per osinfectant Triclummnus foetus in 4 mice 1 2 X 150 O 0 0 0 2 X 100 0 0 0 O2 X 50 0 0 0 0 2 X 25 0 0 0 O 2 X 12.5 0 0 2 11 2 X 150 0 0 O 0 2 X 1000 0 O 0 2 X 50 0 0 (l 0 2 X 25 2 0 2 1 2 X 12.5 3 4 3 3 infectioncontrols 4 4 4 4 product of the invention:

4-( 1'-methy1-5'-nitroimida1.nly1-2'-methylene-imino)-tetrahydro-1.4-thiazine-1 ldioxide 11 comparative composition: Metronidazol EXAMPLE 2 (test foractivity):

Activity against Entamoeba histolylica was generally tested oncross-bred gold hamsters of both sexes. The body weight of each animalwas generally in the range of from 50 to 60 grams.

The substance to be tested was administered orally by means of anesophagal sound, either in an aqueous solution or, in the case ofsparingly water-soluble compounds, in a Tylose suspension. The overalldosage was administered in four units, the first one two hours prior toinfection, the second one two hours after infection, the third one oneday after infection and the fourth one two days after infection. 4Hamsters were used for each substance to be tested.

Infection was brought about by intrahepatical injection of 130,000infective agents per animal as a suspension in 0.1 ml of TTY medium (E.hist.-Crithidia culture). The standard Metronidazol was administered bythe same route and in the same dosage as the substance to be tested (seeTable 2).

As infection controls were generally used 10 hamsters which were, afterinfection, not treated any more. Another 5 hamsters served as a zerocontrol (animals which were not treated and not infected).

Six days at the earliest and eight days at the latest after infection,all the animals were killed. Subsequently, the livers state was judgedaccording to the degree of icteric necrosis developed. Hamsters whichhad died before were subjected to the same examination.

The liver findings as obtained with the tested compo sition and with thestandard were compared to those of the infection controls. The scheme,according to which the liver findings (with tested composition andstandard) were judged, was the following:

ineffective lcteric necrosis did not show any substantial differencefrom that of infection controls. Possible judgement: 3; 4 (in rarecases: 2), effective: a) faint: lcteric necrosis was less developed thanwith the infection controls. Possible judgement: frequently 2 (in rarecases: 1 b) unsatisfactory: lcteric necrosis was substantially reducedas compared to infection controls. Possible judgement: 0 (in rarecases). predominantly 1: 2 (in rare cases), c) good: no icteric necrosiswas discovered Judgement: 0

TABLE 2:

composition dosage in mg/kg liver findings gold hamster, per osEnlamocha histo- I \'Iiul (extraintestinal) in 4 gold hamsters l 4 X 1500 O 0 0 4 X 0 O 0 0 4 X 50 0 O 0 0 4 X 25 0 0 0 1 ll 4 X O O O 0 4 X 100(l 0 l) 4 X 50 0 O l 0 4 X 25 2 l 0 2 infection controls 3 4 4 4 lproduct of I the invention:

4-(1'-methy1-5'-nitroimidazolyl2'-methylcnc-imino)-tetrahydro-1.4-thiazinc-Lldioxide.11 comparative composition: Metronidazol EXAMPLE 3 (preparation ofactive substances) 1. 4-[1-methyl5'-nitroimidazolyl-methylene-(2')-imino]-tetrahydrol ,4-thiazine-l l -dioxide A solution of 15.0 g (0.1mol) of 4-amino-tetrahydrol,4-thiazine-1,1-dioxide in 60 ml of water wasadded in one portion to a solution of 15.5 g (0.1 mol) oflmethyl-5-nitroimidazolyl-2-aldehyde in 150 ml of ethanol, while somedrops of acetic acid were simultaneously added, and the reaction mixturewas heated to 80C for 10 minutes on a steam bath. The end productprecipitated at once in the form of crystals which, after cooling of thesolution, were suction-filtered, washed with some cold water, ethanoland ether and dried. 26 g of 4-[1-methyl-5-nitroimidazolyl-methylene-(2)- imino]-tetrahydrol,4-thiazine- 1 l -dioxide (corresponding to 91 percent of thetheoretical yield) were obtained in the form ofa yellow finelycrystallized powder which had a decomposition point of 265C.

In the same manner as disclosed above, the following compounds could beobtained, with good yields and high purity:

2. 4-[ l -(2-hydroxyethyl)-5-nitroimidazolyl-2'-methylene-iminol-tetrahydro-1.4-thiazine-1,1-dioxide, decomposition at205C.

3.4-(1'-methyl-5-nitroimidazolyl2'-methyleneimino)-3-methyl-tetrahydro-l,4-thiazine-1.l-dioxide,decomposition at 186C.

4. 4-( l -methyl-5 -nitromidaz olyl-2-methyleneimino)-3-ethyl-tetrahydrol ,4-thiazine- 1 1 -dioxide. decomposition at 222C.

5. 4-( l '-methyl-5'-nitroimidazolyl-2'-methyleneimino)-3-methoxymethyl-tetrahydro-1,4-thiazine-l ,1- dioxide, decomp. at 215C.

6. 4-[1 -cthyl-5 '-nitroimidazolyl-2'-methy1eneiminol-tetrahydro-l,4-thiazine-l .l-dioxide, decomposition at 241C.

PREPARATION OF THE STARTING SUBSTANCES1-methyl-5-nitro-imidazolyl-2-aldehydes of the formula II were obtainedby oxidation of l-methyl-2- hydroxy-methyl-S-nitroimidazoles withmanganese dioxide (cf. German Offenlegungsschrift No. 1,595,928). Thehydroxy methyl compound was obtained by hydroxymethylation of1-methyl-5-nitroimidazole (cf. German Offenlegungsschrift No.1,470,102).

Further starting substances of the formula 11 were the followingaldehydes and their functional derivatives: 1-methy1-5-nitro-imidazolyl-( 2 )-aldehyde, l-ethyl-5-nitroimidazolyl-(2)-aldehyde or l-(2'-hydroxyethyl)-5-nitroimidazolyl-(2)-a1dehyde as well as the monoand diacetals, themonoand dimercaptals and the corresponding monoand diacetates thereof;moreover, correspondingly substituted aldimines. oximes, hydrazones,semi-carbazones, thio-semicarbazones and the correspondingaldehyde-cyano-hydrines or hydrogenosulfite compounds.

The 4-amino-tetrahydro-l ,4-thiazinel l -dioxides used as startingcompounds may be obtained by reacting hydrazine hydrate withperhydro-l,4-oxathiine-4,4- dioxides (1,4-thioxan-l,l-dioxides) (cf.British Pat. No. 874,519), which again are prepared by condensation ofbis-(2-hydroxyethyl)-sulfone with concentrated sulfuric acid.

What is claimed is: l. A 4-( l '-alkyl-5'-nitroimidazolyl-2-methyleneimino)-tetrahydro-l,4-thiazine-l,l-dioxideof the forin which R stands for a hydrogen atom, a methyl. ethyl or2-hydroxy-ethyl group and R for a hydrogen atom. a methyl, ethyl ormethoxy-methyl group.

2. A compound as claimed in claim 1, which is 4-( 1'- methyl-S-nitroimidazolyl-2 -methylene-imino tetrahydro-l ,4-thiazine-1 l-dioxide.

3. A compound as claimed in claim 1, which is 4-[ l- (2'-hydroxyethyl)-5 -nitroimidazolyl-2methyleneimino]-tetrahydro-1,4-thiazine-l,l-dioxide.

4. A compound as claimed in claim 1, which is 4-( l methyl-S-nitroimidazolyl-2-methylene-imino )-3 methyl-tetrahydrol ,4-thiazinel l-dioxide.

5. A compound as claimed in claim 1, which is 4-( l methyl-5'-nitroimidazolyl-2 '-methylene-imino )-3 ethyl-tetrahydrol,4-thiazine-l l -dioxide.

6. A compound as claimed in claim 1, which is 4-( 1 methyI-S'-nitroimidazolyl-2 '-methylene-imino)-3- methoxymethyl-tetrahydrol,4-thiazine-l 1 -dioxide.

7. A compound as claimed in claim 1, which is 4-( l ethyl-5'-nitroimidazolyl-2-methylene-imino) tetrahydro-1,4-thiazine-1,l-dioxide.

1. A4-(1''-ALKYL-5''-NITROMIDAZOLYL-2''-METHYLENE-IMINO)TETRAHYDRO-1,4-THIAZINE-1,1-DIOXIDEOF THE FORMULA I
 2. A compound as claimed in claim 1, which is4-(1''-methyl-5''-nitroimidazolyl-2''-methylene-imino)-tetrahydro-1,4-thiazine-1,1-dioxide.
 3. A compound as claimed in claim 1, which is4-(1''-(2''''-hydroxyethyl)-5''-nitroimidazolyl-2''-methylene-imino)-tetrahydro-1,4-thiazine-1,1-dioxide.
 4. A compound as claimed in claim 1, which is4-(1''-methyl-5''-nitroimidazolyl-2''-methylene-imino)-3-methyl-tetrahydro-1,4-thiazine-1,1-dioxide.
 5. A compound as claimed in claim 1, which is4-(1''-methyl-5''-nitroimidazolyl-2''-methylene-imino)-3''-ethyl-tetrahydro-1,4-thiazine-1,1-dioxide.
 6. A compound as claimed in claim 1, which is4-(1''-methyl-5''-nitroimidazolyl-2''-methylene-imino)-3-methoxymethyl-tetrahydro-1, 4-thiazine-1,1-dioxide.
 7. A compound as claimed in claim1, which is4-(1''-ethyl-5''-nitroimidazolyl-2''-methylene-imino)-tetrahydro-1,4-thiazine-1,1-dioxide.